Effects of terazosin therapy on

EFFECTS OF TERAZOSIN THERAPY ON BLOOD PRESSUREIN MEN WITH BENIGN PROSTATIC HYPERPLASIACONCURRENTLY TREATED WITH OTHER ANTIHYPERTENSIVE MEDICATIONSFRANKLIN C.LOWE,PEGGY J.OLSON,ANDROBERT J.PADLEYABSTRACTObjectives.To review and assess the cardiovascular safety of the alpha 1-blocker terazosin when used to treat symptomatic benign prostatic hyperplasia (BPH)in patients taking concurrent antihypertensive med-ications.Methods.This retrospective analysis focused on blood pressure changes and blood pressure-related side effects in 555of 2084patients randomized to either terazosin or placebo in the Hytrin Community Assessment Trial (HYCAT)study who were following either single or combination antihypertensive regimens (treated patients).We also compared results in normotensive and hypertensive patients,whether treated or not.Results.The addition of terazosin lowered mean systolic blood pressure by 5.3mm Hg for untreated patients and 6.7mm Hg for treated patients.For patients hypertensive on entry,mean reductions in systolic blood pressure in those untreated and treated were 12.1and 11.1mm Hg,respectively.The addition of terazosin to an existing antihypertensive regimen had its greatest impact (a mean reduction of 12.3mm Hg)in those receiving diuretic therapy alone.Diastolic pressure changes followed a similar pattern.The inci-dences of blood pressure-related side effects in patients on terazosin were comparable between untreated (13.5%)and treated patients (14.3%),as were premature withdrawal rates,with 4.2%of untreated patients and 4.5%of treated patients withdrawing due to blood pressure-related side effects.Conclusions.Terazosin can be safely used to treat patients with symptomatic BPH regardless of their blood pressure status and antihypertensive regimen.Terazosin may be safely added to ongoing antihypertensive therapy.UROLOGY 54:81–85,1999.©1999,Elsevier Science Inc.Benign prostatic hyperplasia (BPH)and hyper-tension are prevalent health issues in the older population.1BPH has been reported in autopsies of 88%of men older than 80years of age 2and symp-tomatic BPH occurs in an estimated 50%to 70%of American men older than 50years of age.3Hyper-tension is also prevalent in the older population.In 1993,a survey reported that 50million Americans had a blood pressure greater than 140/90mm Hg.4As with BPH,the prevalence of hypertension in-creases with age;24%of the adult population has hypertension and 53%of those adults are treated with antihypertensive medication.5Estimates that 12%to 25%of men older than 59years may have both BPH and hypertension assume that up to 50%have BPH and 25%to 50%have hypertension.6,7Increased activity of the sympathetic nervous system contributes to both hypertension and the symptoms of BPH.Inhibition of prostatic smooth muscle by alpha-adrenergic blockade increases urinary flow rate and decreases residual bladder volume.8,9Similarly,alpha-adrenergic receptor blockers treat hypertension through vasodilation induced by the blockade of vascular smooth mus-cle.9This study was funded through Abbott Laboratories;Dr.Lowe is a lecturer for the sponsor,Merck and Boehringer-Ingelheim;P.J.Olson and Dr.Padley are employees of the sponsor.This study was presented in part at the American Urological Association Meeting,San Francisco,California,May 1995.From the Department of Urology,St.Luke’s/Roosevelt Hospital Center and Columbia University College of Physicians and Sur-geons,New York,New York;and Department of Statistics and Molecular Therapeutics Venture,Abbott Laboratories,Abbott Park,IllinoisReprint requests:Franklin Lowe,M.D.,M.P.H.,425West 59th Street,3A,New York,NY 10019Submitted:October 28,1998,accepted (with revisions):Janu-ary 19,1999ADULT UROLOGYSeveral previous clinical studies have shown that selective alpha-blockers such as doxazosin and terazosin provide safe and effective treatment for both BPH and hypertension,9–17and recent reports have supported the safety of terazosin for normo-tensive patients with BPH.11,12However,the ad-ministration of these drugs to patients with BPH raises the concern that patients who are taking other antihypertensive drugs,as well as those with normal blood pressure,could experience excessive reductions in blood pressure that would cause hy-potensive symptoms.Since terazosin was approved for the treatment of hypertension in 1987and for BPH in 1993,clinical experience with terazosin administration in normotensive,as well as hyper-tensive,patients has now accumulated.The present study analyzed blood pressure and related data collected in the course of the Hytrin Community Assessment Trial (HYCAT),a large multicenter trial involving more than 2000men older than age 54enrolled at 15academic centers and 143community-based private urology prac-tices.17This trial included 555patients who were already receiving antihypertensive medications to which terazosin or placebo was added.Therefore,this trial provided the opportunity to compare the effects of terazosin and placebo treatment in a large group of hypertensive patients with symptomatic BPH who were also receiving concomitant antihy-pertensive therapy.MATERIAL AND METHODSIn brief,the HYCAT protocol included men older than age 54with symptomatic BPH.Blood pressure measurements and assessments of side effects were performed on entry and at weeks 4,8,17,26,39,and 52(the end of the study).Patients were defined as hypertensive if the admission diastolic blood pressure was 90mm Hg or greater;such patients were enrolled only if their blood pressure was clinically considered under control.Exclusion characteristics pertinent to the present study were (a)recent history of cardiovascular or cerebrovas-cular disease and (b)hypotension or a history of fainting spells.Concomitant administration of diuretics,angiotensin-converting enzyme inhibitors,beta-blockers,and/or calcium channel blockers was allowed,but the protocol did not allow verapamil,alpha-adrenergic antagonists,alpha-agonists,anti-androgen therapy,anticholinergic agents,or androgens.In the HYCAT study,1053men were randomly assigned for 1year to terazosin and 1031to placebo.More than 90%were white;their mean age was 66years.Of the 2084men initially randomized,66were taking al-pha-blockers,and are excluded from this analysis.Of the re-maining 2018men,110did not have both a baseline and a follow-up blood pressure determination.Twelve additional patients were excluded either because they started or discon-tinued antihypertensive therapy during the interval between initial and final blood pressure readings.Therefore,1896men were included in the blood pressure analysis for this study.Baseline mean systolic pressures in the placebo and terazosin groups were 134.9and 134.7mm Hg,respectively;mean changes were decreases of 0.8and 5.5mm Hg,respectively (P Ͻ0.001,analysis of variance).Baseline mean diastolic pressures were 81.1and 80.7mm Hg,respectively;mean de-creases were 1.3and 4.0mm Hg,respectively (P Ͻ0.001).RESULTSTable I shows the initial blood pressure values and changes at follow-up for patients who had been on antihypertensive treatment for at least 1week before administration of the study drug and for all others not receiving a concurrent antihyper-tensive agent.The mean reductions in patients ran-TABLE I.Initial mean values and mean changes in blood pressure stratified by antihypertensivetreatment status and presence or absence of hypertensionPlaceboTerazosin Net Change*P Value †nInitialMean Changen InitialMean ChangeNo antihypertensive treatment Normotensive556547Systolic BP (mm Hg)129.20.5(0.6)128.7Ϫ3.5(0.6)Ϫ4.0Ͻ0.001Diastolic BP (mm Hg)77.10.6(0.4)76.7Ϫ2.4(0.4)Ϫ3.0Ͻ0.001Hypertensive140139Systolic BP (mm Hg)146.2Ϫ5.5(1.4)147.4Ϫ12.1(1.4)Ϫ6.6Ͻ0.001Diastolic BP (mm Hg)93.9Ϫ7.2(0.8)93.4Ϫ10.3(0.8)Ϫ3.10.006Antihypertensive treatment Normotensive183196Systolic BP (mm Hg)136.00.9(1.3)135.5Ϫ5.2(1.2)Ϫ6.0Ͻ0.001Diastolic BP (mm Hg)77.7 1.2(0.7)77.7Ϫ1.8(0.7)Ϫ3.00.004Hypertensive6669Systolic BP (mm Hg)153.7Ϫ5.4(2.4)154.5Ϫ11.1(2.3)Ϫ5.70.09Diastolic BP (mm Hg)96.8Ϫ9.2(1.3)94.6Ϫ9.6(1.3)Ϫ0.50.80K EY :BP ϭblood pressure.Data in parentheses are the standard error of the mean.*Mean change in terazosin group Ϫmean change in placebo group.†Between treatments,based on one-way analysis of variance.domized to terazosin were significantly greater than in those randomized to placebo,but there was not a clinically significant difference between the mean reductions in the terazosin patients being treated and those not being treated for hyperten-sion.Table I also analyzes the population according to presence or absence of treatment and the presence or absence of hypertension at randomization.As expected,mean reductions in systolic and diastolic blood pressure for participants identified as hyper-tensive were greatest for the139participants with hypertension who were initially untreated and ran-domized to terazosin,12.1mm Hg systolic and 10.3mm Hg diastolic.In terms of net reductions (mean change in the terazosin group minus mean change in the placebo group),mean decreases in systolic and diastolic pressures in all terazosin-treated groups were greater than in the corre-sponding placebo-treated patients,but the net mean changes in normotensive patients,whether treated or not,were modest,ranging from4to6 mm Hg systolic and3mm Hg diastolic.Mean changes in blood pressure according to the class of concomitant antihypertensives received are shown in Table II.The mean decrease in sys-tolic pressure among men taking terazosin in com-bination with beta-blockers or diuretics was statis-tically significantly greater than in the placebo group;for diastolic blood pressure,the difference in mean change was only significant for men taking beta-blockers.The addition of terazosin to the reg-imens of those taking diuretics caused the greatest mean reduction in systolic blood pressure,14.2 mm Hg greater than in the placebo group.How-ever,the mean baseline value of the terazosin group on concurrent diuretics(146.6mm Hg)was much higher than the overall initial mean value of 140.4mm Hg for all patients on concurrent anti-hypertensive therapy,suggesting that this group was initially poorly controlled.B LOOD P RESSURE-R ELATED S IDE E FFECTSAdding terazosin to an existing antihypertensive regimen did not seem to increase the incidence of side effects,which was13.5%in all patients not receiving antihypertensive treatment and14.3%in all patients receiving such treatment.The attribut-able risk was actually lower for those taking anti-hypertensives(5.3%versus7.6%)(Table III).The incidence of withdrawals because of side effects in men taking terazosin and being treated for hyper-tension was4.5%,close to the4.2%in those not treated.Table III also shows these results accord-ing to initial blood pressure status.The highest attributable risks for side effects were in the un-treated normotensive patients(8.7%)and in the treated hypertensive patients(7.4%)—a rate about twice that in the untreated hypertensive patients (3.2%).The attributable risk for withdrawals wasTABLE II.Initial mean values and mean changes in blood pressure in patients on concurrentantihypertensive medicationsMedicationPlacebo TerazosinNetChange§P Value* n InitialMeanChange n InitialMeanChangeSystolic Blood Pressure(mm Hg)ACE inhibitors39139.8Ϫ2.9(2.8)44141.8Ϫ7.7(2.7)Ϫ4.80.23 Beta-blockers33136.9 1.9(2.9)46134.9Ϫ7.3(2.5)Ϫ9.30.02 Calcium antagonists43140.40.8(2.8)50140.3Ϫ5.2(2.6)Ϫ6.00.12 Diuretics30138.5 1.9(3.2)30146.6Ϫ12.3(3.2)Ϫ14.20.003 Combination A†48137.4Ϫ1.5(2.5)44139.0Ϫ2.0(2.6)Ϫ0.50.69 Combination B‡56147.9Ϫ3.0(2.6)51142.1Ϫ7.6(2.7)Ϫ4.60.22 All medications249140.7Ϫ0.8(1.1)265140.4Ϫ6.7(1.1)Ϫ5.9Ͻ0.001 Diastolic Blood Pressure(mm Hg)ACE inhibitors3983.0Ϫ2.0(2.0)4485.6Ϫ5.5(1.9)Ϫ3.50.22 Beta-blockers3382.60.5(1.9)4679.1Ϫ4.9(1.6)Ϫ5.40.03 Calcium antagonists4377.4Ϫ0.5(1.7)5081.1Ϫ1.9(1.6)Ϫ1.40.55 Diuretics3083.90.0(1.7)3081.3Ϫ2.5(1.7)Ϫ2.50.32 Combination A†4881.9Ϫ1.2(1.5)4481.5Ϫ2.7(1.6)Ϫ1.50.50 Combination B‡5686.9Ϫ4.3(1.4)5183.7Ϫ5.0(1.5)Ϫ0.70.74 All medications24982.8Ϫ1.6(0.7)26582.1Ϫ3.8(0.7)Ϫ2.30.02 K EY:ACEϭangiotensin-converting enzyme.Data in parentheses are the standard error of the mean.*Between treatments,based on one-way analysis of variance.†A diuretic and one of the following:ACE inhibitor,beta-blocker,or calcium antagonist.‡Any other combination of two or more antihypertensive medications.§Mean change in terazosin groupϪmean change in placebo group.2.6%in the untreated normotensive patients and Ϫ1.5%in the treated hypertensive patients.COMMENTWe present thefirst in-depth analysis of the con-comitant use of terazosin therapy for BPH in pa-tients receiving ongoing antihypertensive therapy. It is also thefirst detailed analysis of the side effects and withdrawal rates for conditions related to blood pressure in the HYCAT study.The two groups potentially at greatest risk of blood pres-sure-related side effects from the administration of terazosin are persons who are normotensive and patients with hypertension successfully treated with other antihypertensive agents.Previous safety analyses and reviews of terazosin therapy11,12did not perform in-depth subset analyses between treated versus untreated hypertensive patients,be-tween normotensive and hypertensive patients,or according to other concomitant medications.In the1165untreated nonhypertensive patients we studied(583receiving terazosin and582place-bo),terazosin produced a small mean drop in sys-tolic and diastolic pressure below the limit of clinical significance.The subset analysis of con-comitant medications showed that the greatest re-duction in systolic blood pressure occurred in those patients taking diuretics alone,a net decrease over the placebo group of14.2mm Hg.This could have been predicted by the fact that patients taking diuretics had the highest mean baseline blood pressure(146.6mm Hg)—confirming that diuret-ics are the least efficacious form of antihyperten-sive therapy.Thus,terazosin therapy for BPH can have an appropriate and beneficial effect on blood pressure when given to treated(especially diuretic-treated)hypertensive patients.Adding terazosin to an existing antihypertensive regimen had little impact on the rate of side effects. Also,the premature termination rate,which re-flects the significance and severity of side effects, was increased by the addition of terazosin only by an attributable risk of2.2%for untreated and1.9% for treated patients,suggesting that most of the blood pressure-related side effects of terazosin are mild to moderate.Terazosin can be safely used to treat men with symptomatic BPH,irrespective of their blood pressure status and antihypertensive regimens,and may be safely added to ongoing an-tihypertensive regimens.The present study extends our knowledge about the use of terazosin for BPH.In terms of treatment-emergent side effects,in the2084-patient HYCAT study,the rate of myocardial infarction was lower for terazosin-treated patients.In the placebo group,10patients suffered myocardial infarctions compared with only1in the terazosin group dur-ing the1-year trial.This potential cardioprotectiveTABLE III.Incidence of blood pressure-related side effects and withdrawals*Treatment and Blood Pressure StatusPlacebo TerazosinP Value†nIncidence(n)nIncidence(n)AttributableRisk(%)No antihypertensive treatment729734OverallSide effects‡43(5.9)99(13.5)7.6Ͻ0.001 Withdrawals15(2.1)31(4.2) 2.20.02 Normotensive582583Side effects36(6.2)87(14.9)8.7Ͻ0.001 Withdrawals14(2.4)29(5.0) 2.60.028 Hypertensive147151Side effects7(4.8)12(7.9) 3.20.34 Withdrawals1(0.7)2(1.3)0.6 1.0 Antihypertensive treatment268287OverallSide effects24(9.0)41(14.3) 5.30.06 Withdrawals7(2.6)13(4.5) 1.90.26 Normotensive195210Side effects18(9.2)29(13.8) 4.60.17 Withdrawals4(2.1)11(5.2) 3.20.12 Hypertensive7377Side effects6(8.2)12(15.6)7.40.21 Withdrawals3(4.1)2(2.6)Ϫ1.50.68 Numbers in parentheses are percentages.*Patients who began or discontinued antihypertensive medication during the study are included and assigned according to their initial status.†From Fisher’s exact test for comparison between groups.‡Number of patients with a blood pressure-related side effect(dizziness,postural hypotension,vertigo,syncope,or postural dizziness).result had not been identified in previous shorter, smaller studies.Although alpha-blockers have a favorable effect on serum cholesterol(Ϫ5%),tri-glycerides(Ϫ10%),and low-density lipoproteins (Ϫ6%)and increase the ratio of high-density li-poprotein to cholesterol(ϩ5%),11it is unlikely that these were important factors because of the relatively short-term nature of the trial.In fact,the potential cardioprotective effect was probably due to the better control of the patients’blood pressure, especially for those with clinical hypertension. 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